Traditionally medicinal chemists have sought to discover and develop therapeutic agents that operate on a single target with high selectivity and affinity. However, it has frequently been found that compounds affecting multiple targets (i.e., “dirty drugs”) are superior to those with narrower profiles. Furthermore, advances in “omics” have shown that many diseases are extremely complex. For example, cancer can involve the disregulation of as many as 500 gene products. Thus, a “magic bullet” approach has serious limitations. For these reasons there is currently underway a shift in paradigm from “single drug, single target” to polypharmacologic or, the more rational, multi-target drug discovery (MTDD) approaches. MTDD is not an easy strategy because of the requirement to design drugs that modulate two, three, or multiple disease targets simultaneously. It is very difficult to create fused, hybrid structures where different molecular fragments or segments recognize different targets. A simpler strategy involves tethering together multiple structural domains that each possess different biological activities. These ligands may be the conjugate of two known inhibitors, such as two proteins in a particular signaling pathway, or they may be a binding unit and a reactive moiety covalent linked. Either way, effective examples of this kind of therapy are still needed if this approach is to make it to the clinic.
Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disorder characterized by a range of symptoms that include muscle weakness (myopathy), difficulty relaxing muscles (myotonia), progressive muscle wasting (atrophy), cataracts, cardiac defect, and insulin dependent diabetes. There is an urgent need to discover lead agents for treating DM1 because it affects about 1 in 8,000 people, yet it remains incurable with no direct therapeutic options.
DM1 results from a progressive expansion of the trinucleotide CTG repeat in the 3′-untranslated region of the dystrophia myotonia protein kinase (DMPK) gene on chromosome 19q13.3. The number of CTG repeats is less than 35 in healthy people, and ranges from 50 to thousands in DM1 patients. The molecular origin of DM1 was previously attributed to three possible mechanisms: (1) DMPK haploinsufficiency, (2) decreased expression of neighboring genes, including SIX5 and DMAHP, and (3) a gain-of-function for the expanded RNA transcript (rCUGexp). Recent studies have argued against the first two hypotheses, leaving the third mechanism as the favored one for therapeutic intervention.
The gain of function model involves expanded rCUG repeats forming stable stem-loop structures with U-U mismatches flanked by G-C and C-G base pairs, and sequestering important proteins. Key among these proteins is the muscleblind-like (MBNL) protein, a key alternative splicing regulator. The loss of MBNL1 results in the abnormal alternative splicing of more than 100 pre-mRNAs, including the cardiac troponin T (cTNT), insulin receptor (IR) and chloride channel 1 (ClC-1). Supporting the toxic RNA model is the finding that overexpression of MBNL1 protein in the skeletal muscle of a DM1 mouse model relieved the myotonia and abnormal RNA splicing. The MBNL1-rCUGexp complex formation has emerged as a key therapeutic target for DM1. Because there are currently no effective therapies for DM1, there is an urgent need for a new compounds and methods for the study and treatment of the disease.